A novel mechanism for faithful chromosome segregation compromised in cancer cells
New cells arise from existing ones through cell division. This is a continuous, frequent and ubiquitous process which starts at conception and ends at death. There are an estimated 37 trillion cells in the tissues and organs of the human body, each of which originates from one cell dividing into two.
When cell division goes wrong, it can generate new cells with an abnormal number of chromosomes, a phenomenon known as aneuploidy. The frequency at which chromosome segregation errors occur is known as chromosomal instability (CIN). In some cases, for example a developing embryo, this can promote spontaneous abortion and in others, it can contribute to human diseases such as cancer. Aneuploidy and CIN are indeed hallmarks of particularly aggressive tumors.
Faithful chromosome segregation is fully dependent on the transient assembly of a microtubule-based molecular machine, the bipolar spindle. Microtubules are dynamic filaments that attach each chromosome to the spindle poles and provide the support and forces required for their segregation to the new daughter cells. Their dynamic properties need to be finely regulated so they remain stable enough to move and align the chromosomes, but also dynamic enough to allow for correction of any erroneous attachments before chromosomes are pulled apart and segregated.
We recently found that the polyglutamylation of the spindle microtubules defines finely their dynamics and thereby secures faithful chromosome segregation. This specific post-translational modification is driven by the glutamylase TTLL11. The polyglutamylation of the spindle microtubules is reduced in cancer cells that are characterized by high levels of aneuploidy arising from chromosome segregation defects. Consistently, TTLL11 expression is systematically downregulated in human cancers. Altogether these data suggest novel potential therapeutic approaches to fight cancer.